HU217298B - Substituted aminoalkylaminopyridil-methylthiobenzimidazole- and -imidazo [5,4-b]piridine derivatives, preparation and use thereof, pharmaceutical compositions containing these compounds - Google Patents

Abstract

PCT No. PCT/EP94/03911 Sec. 371 Date May 31, 1996 Sec. 102(e) Date May 31, 1996 PCT Filed Nov. 26, 1994 PCT Pub. No. WO95/15324 PCT Pub. Date Jun. 8, 1995Compounds of formula I <IMAGE> (I) wherein R1, R2, R3, R4, R5, R6, X, n and A have the meanings as given in the description, can be used for combatting Helicobacter bacteria.

Description

FIELD OF THE INVENTION The present invention relates to substituted aminoalkylaminopyridylmethylthiobenzimidazole and imidazo [5,4-b] pyridine derivatives, their preparation and their use, and to pharmaceutical compositions containing them.

The present invention relates to novel compounds useful as active ingredients in the pharmaceutical industry for the preparation of pharmaceutical compositions.

Known technical background

WO 92/12976 discloses certain substituted 2-pyridylmethylthio- and sulfmyl] benzimidazoles for use against Helicobacter bacteria. These compounds are useful in the prophylaxis and treatment of many gastric diseases. .

Description of the Invention

SUMMARY OF THE INVENTION The present invention relates to compounds of formula I in the formula

R ¹ is hydrogen;

R ² is hydrogen;

R ³ is halogen;

R ⁴ is C 1-7 alkyl;

A is C 1-7 alkylene;

X is = N- or = CH-;

R ⁵ is C 1 -C 7 alkyl, C 3 -C 8 cycloalkyl or Ar (C 1 -C 4 alkyl);

R ⁶ is C 1 -C 7 alkyl, C 3 -C 8 cycloalkyl or Ar (C 1 -C 4 alkyl);

Ar is phenyl, furyl or phenyl substituted by R ⁷ , R ⁸ and R ⁹ ; obsession

R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form an unsubstituted or substituted 6-membered heterocycle, namely piperidino, piperazino,

Forms a 1,2,3,4-tetrahydroquinolino or 1,2,3,4-tetrahydroisoquinolino group; wherein the substituted piperidino group is one or two identical or different C 1-4 alkyl,

C 1 -C 4 alkoxy, phenyl or R ⁷ , R ⁸ and R ⁹ substituted phenyl and / or phenyl (C 1-4 alkyl) substituents;

the substituted piperazino group at the 4-position is C 1-4 alkyl, (C 1-4 alkoxy) carbonyl, phenyl, R ⁷ , R ⁸ and R ⁹ substituted phenyl, phenyl (C 1-4 alkyl) -; or on the phenyl ring substituted with R ⁷ , R ⁸ and R ⁹ substituted phenyl (C 1 -C 4 alkyl) or benzhydryl;

the substituted 1,2,3,4-tetrahydroquinolino group has one or two identical or different C 1-4 alkyl and / or halogen substituents; the substituted 1,2,3,4-tetrahydroisoquinolino group on the benzene ring has one or two hydroxy, C 1-4 alkoxy and / or di (C 1-4 alkyl) amino substituents;

R ⁷ is hydrogen, C 1-4 alkyl, C 1-4 alkoxy, halogen or nitro;

R ⁸ is hydrogen, C 1-4 alkyl,

C 1-4 alkoxy, halogen or nitro; and

R ⁹ is hydrogen or trifluoromethyl and refers to their salts.

As used herein, the term "C 1-4 alkyl" refers to straight or branched chain alkyl groups (e.g., butyl, isobutyl, secondary butyl, tert-butyl, propyl, isopropyl, ethyl or methyl).

The term "C 1 -C 4 alkoxy" refers to alkyl groups (e.g., methoxy or ethoxy) attached via an oxygen atom as defined above.

The term "halogen" refers to bromine, chlorine and fluorine.

"C 1-7 -alkyl" refers to straight or branched chain C 1-7 -alkyl (e.g., heptyl, hexyl, neopentyl, isopentyl, pentyl, butyl, isobutyl, secondary butyl, tertiary butyl). , propyl, isopropyl, ethyl and methyl).

The term "C 1-7 alkylene" refers to straight or branched C 1-7 alkylene groups such as methylene (-CH ₂ -), ethylene (-CH ₂ -CH ₂ -), trimethylene (-CH ₂ -CH) ₂ -CH ₂ -), tetramethylene (-CH ₂ -CH ₂ -CH ₂ -CH ₂ -), 1,2-dimethylethylene [-CH (CH ₃ ) -], Ι, Γ-dimethylethylene [ -C (CH ₃ ) ₂ CH ₂ -], 2,2-dimethylethylene [-CH ₂ -C (CH ₃ ) ₂ -], isopropylidene [-C (CH ₃ ) ₂ -], 1-methyl ethylene [-CH (CH ₃ ) CH ₂ -], pentamethylene (-CH ₂ -CH ₂ -CH ₂ -CH ₂ -CH ₂ -), hexamethylene (-CH ₂ -CH ₂ -CH ₂ -CH) ₂ -CH ₂ -CH ₂ -) and heptamethylene (-CH ₂ -CH ₂ -CH ₂ -CH ₂ -CH ₂ -CH ₂ -CH ₂ -).

Examples of "C3-C8 cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

The term "Ar (C1-C4) alkyl" refers to C1-C4-Ar substituted alkyl groups as defined above (e.g., phenethyl, benzyl, and 2-furylmethyl (furfuryl)).

The term "(C 1 -C 4) alkoxy carbonyl" refers to the C 1 -C 4 alkoxy group attached to the carbonyl group as defined above (e.g., methoxycarbonyl, ethoxycarbonyl).

The term "di (C 1 -C 4 alkyl) amino" refers to the above-defined amino groups substituted by two identical or different (C 1 -C 4) alkyl groups (e.g., dimethylamino, diethylamino or diisopropylamino). group).

Examples of phenyl groups substituted by R ⁷ , R ⁸ and R ⁹ include 3,4-dimethoxy, 2-methoxy, 2-ethoxy, 3-methoxy, 4-methoxy, 4-fluoro, 4-chloro. -, 2-chloro, 3-chloro, 3,4-dichloro, 3- (trifluoromethyl), 2- (trifluoromethyl), 2-methyl, 3-methyl, 4-methyl, 2,3-dimethyl, 2,4-dimethyl, 3,4-dimethyl, 2,5-dimethyl, 4nitro and 2,6-dinitro-4- (trifluoromethyl) phenyl.

Representative substituted piperidino groups include, for example, 2-n-propylpiperidino, 5-ethyl-2-methylpiperidino, 4-n-propyl

HU 217 298 Β piperidino, 4- (3-phenylpropyl) piperidino, 4-ethoxy-4-phenyl-piperidino, 4,4-dimethyl-piperidino, 4-phenyl-4-propoxy-piperidino, 2 6-dimethyl-piperidino, 2-ethyl-2-methyl-piperidino, 2-methyl-piperidino, 2,6-dimethyl-piperidino,

2-ethylpiperidino and 4-benzylpiperidino.

Exemplary substituted piperazino groups include 4-methylpiperazino, 4- {2- [2- (trifluoromethyl) phenyl] ethyl} piperazino, 4-phenylpiperazino, 4- (2- methylphenyl) piperazino, 4- (2,3-dimethylphenyl) piperazino, 4- (2-chlorophenyl) piperazino, 4- (2-methoxyphenyl) piperazino, 4- (2) ethoxyphenyl) piperazino, 4- (3-chlorophenyl) piperazino, 4- (4-fluorophenyl) piperazino, 4- (4-chlorophenyl) piperazino, 4- (4-methoxyphenyl) piperazino, 4- (2,4-dimethylphenyl) piperazino, 4- (3,4-dichlorophenyl) piperazino, 4- (3,4-dimethylphenyl) piperazine, 4-benzylpiperazine -, 4-propyl-piperazino, 4- (3-methyl-phenyl) -piperazino, 4- (3-methoxyphenyl) piperazino, 4- (4-methyl-phenyl) -piperazine, 4- (2,5- dimethylphenyl) piperazino, 4-benzhydrylpiperazine, 4-n-butylpiperazine, 4-isobutylpiperazine, 4-tert-butylpiperazine, 4- [3- (trifluoromethyl) -phenyl] piperazino, 4- (1-phenylethyl) piperazino, 4- (2-phenylethyl) piperazino, 4- (3,4-dimethoxyphenyl) piperazine, 4-isopropyl-piperazino- . 4- [2,6-dinitro-4- (trifluoromethylphenyl] piperazino] and 4- (ethoxycarbonyl) piperazino.

Examples of substituted 1,2,3,4-tetrahydroquinolino groups include 2-methyl-1,2,3,4-tetrahydro-1-quinolinyl, 6-methyl-1,2,3,4-tetrahydro-1. quinolinyl, 6-fluoro-2-methyl-1,2,3,4-tetrahydro-1-quinolinyl, 4-methyl-1,2,3,4-tetrahydro-1-quinolinyl, and 2-fluoro-6 methyl-1,2,3,4-tetrahydro-1-quinolinyl.

Exemplary substituted 1,2,3,4-tetrahydroisoquinolino groups include 6,7-dimethoxy-1,2,3,4-tetrahydro-2-isoquinolinyl and 6,7-dihydroxy-1,2 , 3,4-tetrahydro-2-isoquinolinyl radical.

The salts of the compounds of formula I may be any acid addition salt. Particularly preferred are the pharmaceutically acceptable salts of the inorganic and organic acids used in the pharmaceutical industry. Non-pharmaceutically acceptable salts, such as those resulting from the industrial preparation of the compounds of this invention, are converted into pharmaceutically acceptable salts by methods known to those skilled in the art. The salts can be both water soluble and water insoluble acid addition salts. For example, the following acids may be used for the salt formation: hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, Dgluconic acid, benzoic acid, 2- (4-hydroxybenzoyl) benzoic acid, butyric acid, sulfosalicylic acid, maleic acid, lauric acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid and

3-Hydroxy-2-naphthoic acid. In preparing the salts, the acids may be used in equimolar or non-equimolar proportions, depending on whether the acid is monobasic or polybasic or the desired salt.

Particularly preferred compounds of the formula I and their salts are those wherein R ¹ is hydrogen, R ² is hydrogen, R ³ is chlorine, R ⁴ is C 1 -C 4 alkyl, A is ethylene or propylene and X is = CH-.

A preferred group of compounds of formula I are those compounds wherein R ¹ is hydrogen;

R ² is hydrogen;

R ³ is halogen;

R ⁴ is C 1-4 alkyl;

A is C 2 -C 4 alkylene; and

X is = N- or = CH-; and

R ⁵ is C 1 -C 4 alkyl or Ar (C 1 -C 4 alkyl); and R ⁶ is Ar (C 1 -C 4 alkyl);

Ar is phenyl, furyl or phenyl substituted by R ⁷ , R ⁸ and R ⁹ ; or R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form an unsubstituted or substituted 6-membered heterocycle, namely piperidino, piperazino,

Forms a 1,2,3,4-tetrahydroquinolin-1-yl or 1,2,3,4-tetrahydroisoquinolin-2-yl group; wherein the substituted piperidino group is one or two identical or different C 1 -C 4 alkyl, C 1 -C 4 alkoxy, phenyl or R ⁷ , R ⁸ and R ⁹ substituted phenyl and / or C 1 -C 4 alkyl; the substituted piperazino group at the 4-position is C 1-4 alkyl, (C 1-4 alkoxycarbonyl, phenyl, R ⁷ , R ⁸ and R ⁹ substituted phenyl, phenyl (1-4); (C 1 -C 4 alkyl) or substituted on the phenyl ring with R ⁷ , R ⁸ and R ⁹ substituted phenyl (C 1 -C 4 alkyl) or benzhydryl;

the substituted 1,2,3,4-tetrahydroquinolin-1-yl group has one or two identical or different C 1-4 alkyl and / or halogen substituents;

the substituted 1,2,3,4-tetrahydroisoquinolin-2-yl group has one or two hydroxy, C 1 -C 4 alkoxy and / or di (C 1 -C 4 alkyl) amino substituents on the benzene ring;

R ⁷ is hydrogen, C 1-4 alkyl,

C 1-4 alkoxy, halogen or nitro;

R ⁸ is hydrogen, C 1-4 alkyl,

C 1-4 alkoxy, halogen or nitro; and

R ⁹ is hydrogen or trifluoromethyl.

A particularly preferred group of compounds of formula I are those compounds and salts thereof in which

R ¹ is hydrogen;

R ² is hydrogen;

R ³ is chlorine;

R ⁴ is C 1-4 alkyl;

A is ethylene or propylene; and X is = CH-; and

R ⁵ is C 1 -C 4 alkyl or benzyl; and

R ⁶ is Ar (C 1 -C 4) alkyl;

Ar is phenyl or phenyl; obsession

HU 217 298 Β

R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form an unsubstituted or substituted 6-membered heterocycle, which is piperidino, piperazino, 1,2,3,4-tetrahydroisoquinolin-2-yl, wherein the substituted piperidino group is phenyl - or contains a benzyl substituent; the substituted piperazino group in the 4-position carries a phenyl, R ⁷ , R ⁸ and R ⁹ substituted phenyl or benzyl substituent; and the substituted 1,2,3,4-tetrahydroisoquinolino group has one or two C 1 -C 4 alkoxy substituents on the benzene ring; and

R ⁷ is hydrogen or C 1 -C 4 alkoxy;

R ⁸ is hydrogen; and

R ⁹ is hydrogen.

The compounds of formula I according to the invention

- where R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , X and A are as defined above - and their salts can be prepared by the following processes:

a) reacting a mercaptobenzimidazole of formula II wherein R ¹ , R ² and X are as defined above with a picoline derivative of formula III: wherein R ³ , R ⁴ , R ⁵ , R ⁶ and A are as defined above and Y is a suitable leaving group -; obsession

b) reacting a compound of formula IV wherein R ¹ , R ² , R ³ , R ⁴ , X and A are as defined above and Z is a suitable leaving group, with an amine of formula HNR ⁵ R ⁶

- R ⁵ and R ⁶ are as defined above; and optionally converting the resulting compound of formula I into a salt and / or releasing the compound of formula I from a salt obtained.

In the above processes, the starting materials may be used in the form of the free compound or its salt.

The leaving group at Y or Z is preferably a halogen (especially chlorine) or hydroxyl group activated by esterification (e.g. p-toluenesulfonic acid).

In process (a), the reaction of the compounds of the formulas II and III is carried out in a suitable, preferably polar, protic or aprotic solvent (e.g. methanol, ethanol, isopropanol, dimethylsulfoxide, acetone, dimethylformamide or acetonitrile), in the presence or absence of water. The reaction may be carried out in the presence of an acid acceptor. For this purpose, for example, alkali metal hydroxides (e.g. sodium hydroxide), alkali metal carbonates (e.g. potassium carbonate) or tertiary amines (e.g. pyridine, triethylamine or ethyldiisopropylamine) may be used. Alternatively, the reaction may be carried out in the absence of an acid scavenger and, depending on the nature of the starting materials.

optionally, the acid addition salts can be isolated in a particularly pure state. The reaction may be carried out at 0-150 ° C. In the presence of an acid acceptor, it is preferable to operate at a temperature of from 20 to 80 ° C, and in the absence of an acid binder, preferably from 60 to 120 ° C, particularly preferably at the boiling point of the solvent. The reaction time is 0.5-30 hours.

The reaction of the compound of formula AIV with the amine of formula HNR ⁵ R ⁶ may be carried out under the conditions described for the reaction of compounds of formula II and III. The reaction is preferably carried out in the absence of a separate solvent in excess of the amine. An excess of an amine of formula HNR ⁵ R ⁶ may serve as both an acid scavenger and a solvent. The reaction temperature is 60-180 ° C, preferably 80-160 ° C.

The starting materials of formula II are known, for example, from German Patent Publication No. 3 404 610 or European Patent Application No. 134400. The starting materials of formula III can be prepared, for example, as described in the Examples or analogously to those described in European Patent No. 184,322.

The starting materials of formula IV are preferably prepared from known starting materials or analogous starting materials as described in the Examples.

Further details of the present invention are set forth in the following examples, without limiting the invention to the examples. The other compounds and starting materials of the present invention may be prepared in an analogous manner to that described in the Examples.

The composition of the solvent mixtures given in the examples is by volume / volume.

Examples

end products

Example 1

2- {3-Chloro-4- [N- [2- (N-benzyl-N-ethylamino) -ethyl] -N-methyl-amino] -2-pyridylmethyl-thio} -1H-benzimidazole; trihydrochloride

500 mg (1.24 mmol) of 2- {3-chloro-4- [N- (2-chloroethyl) -N-methylamino] -2-pyridyl} methylthio-1H-benzimidazole in 15 mL of N-ethyl The mixture was heated at 140 ° C for 4.5 hours in -N-benzylamine. The excess N-ethyl-N-benzylamine was distilled off under high vacuum. The residue is chromatographed on silica gel, eluting with 97 ml of dichloromethane / methanol (1 ml / l concentrated aqueous ammonium hydroxide). The pure fractions were combined and concentrated in vacuo. The residue was dissolved in a little methanol and 1 mL of saturated ethereal hydrogen chloride and diisopropyl ether was added. The precipitated solid was filtered off and dried in vacuo. Yield: 200 mg (28%) of the title compound as a colorless solid, m.p.> 180 ° C (dec.).

Example 2

2- {3-Chloro-4- [N- [2- (l, 2,3,4-tetrahydro-isoquinolin-2-yl) ethyl] -N-methylamino] -2-yl-methylthio} - benzimidazole trihydrochloride

500 mg 2- {3-chloro-4- [N-2- (chloroethyl) -N-methylamino] -2-pyridylmethylthio} -1H-benzimidazole in 10 ml

1,2,3,4-Tetrahydroisoquinoline was heated at 100 ° C for 2.5 hours. The excess amine was distilled off under high vacuum. The oily residue was chromatographed on silica gel

It is eluted with petroleum ether / ethyl acetate / methanol (65: 30: 5) containing 1 ml of concentrated aqueous ammonium hydroxide per liter. The pure fractions collected were combined and concentrated in vacuo. The residue was dissolved in a small amount of methanol (5 mL), mixed with ethereal hydrogen chloride and a little diisopropyl ether was added. The precipitated solid was filtered and dried under high vacuum. Yield: 460 mg (65%), m.p.> 240 ° C (dec.).

Example 3

2- {3-Chloro-4- [N- [2- (1,2,3,4-tetrahydroisoquinolin2-yl) ethyl] -N-methylamino] -2-pyridylmethylthio} - lHbenzimidazol

0.1 g of 2- {3-chloro-4- [N- [2- (1,2,3,4-tetrahydroisoquinolin-2-yl) ethyl] -N-methylamino] -2-pyridyl Methylthio} -1H-benzimidazole trihydrochloride was dissolved in 7 ml water and 1 ml saturated aqueous sodium bicarbonate solution. The precipitated colorless precipitate was collected, washed with distilled water and dried at 60 ° C in vacuo. Yield: 70 mg (87%), m.p.> 88 ° C (dec.).

Example 4

2- {3-Methyl-4- [N- [2- [N- (2-furfuryl) -N-methylamino] ethyl] -N-methylamino] -2-pyridylmethylthio} -1H-benzimidazole trihydrochloride

In a manner analogous to that described in Example 1, 1.5 g of 2- {3-chloro-4- [N- (2-chloroethyl) -N-methylamino] -2-pyridylmethylthio} was obtained. 1H-benzimidazole and 2 ml of N-furfuryl-N-methylamine were heated at 100 ° C for 4 hours. Melting point: 212 DEG C. (dec.). Yield: 1.35 g (64%).

Example 5

2- {3-Chloro-4- [N- [2- (l, 2,3,4- (l, 2,3,4-tetrahydroisoquinolin-2-yl) ethyl] -N-methylamino] - 2-Pyridylmethylthio} -1H-imidazole [5,4-b] pyridine

The title compound was obtained in a manner analogous to that described in Example 2, using 2- {3-chloro-4- [N- (2-chloroethyl) -N-methylamino] -2-pyridylmethylthio} -1H-. by reaction of imidazo [5,4-b] pyridine and 1,2,3,4-tetrahydroisoquinoline. Chromatography on silica gel eluting with 4: 1 ethyl acetate: methanol gave a colorless powder, m.p. 128-129 ° C (52%).

Example 6

2- {3-Chloro-4- [N- [2- (N-benzyl-N-methylamino) ethyl] N-methylamino] -2-pyridylmethylthio} -1H-benzimidazole trihydrochloride

In a manner analogous to that described in Example 1, the title compound was treated with 2- {3-chloro-4- [N- (2-chloroethyl) -N-methylamino] -2-pyridylmethylthio} -1 H benzimidazole and N-methyl-N-benzylamine. After purification by silica gel chromatography, the product is converted to the trihydrochloride. M.p. 237-240 ° C (dec.), Amorphous powder.

Example 7

2- {3-Chloro-4- [N- [2- (N, N-dibenzylamino) ethyl] -N-methylamino] -2-pyridylmethylthio} -1H-benzimidazole trihydrochloride. In a manner analogous to that described in Example 2, 2- {3-chloro-4- [N- (2-chloroethyl) -N-methylamino] -2-pyridylmethylthio} -1H-benzimidazole and dibenzyl- amine. Chromatography on silica gel eluting with petroleum ether / ethyl acetate 1: 1 gave a colorless amorphous powder.

Example 8

2- {3-Chloro-4- [N - [2- (N, N-diethylamino) ethyl] -N-methylamino] -2-pyridylmethylthio} -1H-benzimidazole trihydrochloride

In a manner analogous to that described in Example 1, the title compound was treated with 2- {3-chloro-4- [N- (2-chloroethyl) -N-methylamino] -2-pyridylmethylthio} -1 H benzimidazole and diethylamine. Chromatography on silica gel eluting with 4: 1 ethyl acetate: methanol followed by conversion to trihydrochloride gave an amorphous powder melting at 245.7 ° C (dec).

Example 9

2- {3-Chloro-4- [N- [2- (N-methyl-N-phenethyl-amino) ethyl] -N-methylamino] -2-pyridyl-thio} methyl-lH-benzimidazole trihydrochloride

In a manner analogous to that described in Example 1, the title compound was treated with 2- {3-chloro-4- [N- (2-chloroethyl) -N-methylamino] -2-pyridylmethylthio} -1 H benzimidazole and N-methyl-N-phenethylamine. Chromatography on silica gel, elution with 9: 1 ethyl acetate: methanol and conversion to the trihydrochloride gave an amorphous powder melting at 239-241 ° C (dec).

Example 10

2- {3-Chloro-4- [N- [2- (N-furfuryl-N-methylamino) ethyl] -N-methylamino] -2-pyridylmethylthio} -1H-benzimidazole trihydrochloride

In a manner analogous to that described in Example 1, the title compound was treated with 2- {3-chloro-4- [N- (2-chloro-1) -N-methylamino] -2-pyridylmethylthio} -1 H benzimidazole and N-furfuryl-N-methylamine. Chromatography on silica gel eluting with 9: 1 ethyl acetate: methanol followed by conversion to the trihydrochloride gave a brownish amorphous powder melting at 239-241 ° C.

Example 11

2- {3-chloro-4- [N- [2- (4-phenylpiperidino) ethyl] -N-methylamino] -2-pyridylmethylthio} -1H-benzimidazole In a manner analogous to that described in Example 2, 2- {3-chloro-4- [N- (2-chloroethyl) -N-methylamino] -2-pyridylmethylthio} -1H-benzimidazole and 4- by reaction of phenylpiperidine. Chromatography on silica gel with ethyl acetate 3: 1

Elution with acetate / methanol gave an amorphous yellow powder melting at 55-65 ° C.

Example 12

2- {3-Chloro-4- [N- [2- (4-benzylpiperidino) ethyl] -N-methylamino] -2-pyridylmethylthio} -1H-benzimidazole. In a manner analogous to that described in Example 2b, 2- {3-chloro-4- [N- (2-chloroethyl) -N-methylamino] -2-pyridylmethylthio} -1H-benzimidazole and 4-benzylpiperidine reaction. Chromatography on silica gel eluting with 4: 1 ethyl acetate / methanol gave a dense, yellowish oil.

Example 13

2- {3-Chloro-4- [N- (2-piperidinoethyl) -N-methylamino] 2-pyridylmethylthio} -1H-benzimidazole

In a manner analogous to that described in Example 2, the title compound was treated with 2- {3-chloro-4- [N- (2-chloroethyl) -N-methylamino] -2-pyridylmethylthio} -1 H by reaction of benzimidazole and piperidine. Chromatography on silica gel eluting with 4: 1 ethyl acetate / methanol gave a dense yellowish oil.

Example 14

2- {3-Chloro-4- [N- [2- (6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinolin-2-yl) -ethyl] -N-methyl-amino] -2-pyridine 1- methyl 1-110} -1H-benzimidazole

In a manner analogous to that described in Example 2, the title compound was treated with 2- {3-chloro-4- [N- (2-chloroethyl) -N-methylamino] -2-pyridylmethylthio} -1 H-. benzimidazole and 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline. Chromatography on silica gel eluting with 4: 1 ethyl acetate / methanol gave a dense yellowish oil.

Example 75

2- {3-Chloro-4- [N- [2- (4-phenylpiperazino) ethyl] -N-methylamino] -2-pyridylmethylthio} -1H-benzimidazole hydrochloride

In a manner analogous to that described in Example 1, the title compound was treated with 2- {3-chloro-4- [N- (2-chloroethyl) -N-methylamino] -2-pyridylmethylthio} -1 H benzimidazole and 4-phenylpiperazine. Chromatography on silica gel, eluting with 4: 1 ethyl acetate: methanol and conversion to the hydrochloride gave the amorphous powder, m.p. 212-215 ° C (dec).

Example 16

2- {3-Chloro-4- [N- [2- (4-benzyl-piperidino) -ethyl] -N-methyl-amino] -2-pyridylmethyl-thio} -1H-benzimidazole trihydrochloride

In a manner analogous to that described in Example 1, the title compound was treated with 2- {3-chloro-4- [N- (2-chloroethyl) -N-methylamino] -2-pyridylmethylthio} -1 H benzimidazole and 4-benzylpiperazine. Chromatography on silica gel eluting with 4: 1 ethyl acetate: methanol followed by conversion to the trihydrochloride gave an amorphous powder melting at 227-230 ° C (dec.).

Example 17

2- {3-Chloro-4- [N - [2- [4- (2-methoxyphenyl) piperazino] ethyl] -N-methylamino] -2-pyridylmethylthio} -1H-benzimidazole- trihydrochloride The title compound was obtained in a manner analogous to that described in Example 1, using 2- {3-chloro-4- [N- (2-chloroethyl) -N-methylamino] -2-pyridylmethylthio} -1H. benzimidazole and 4- (2-methoxyphenyl) piperazine. Chromatography on silica gel and elution with 9: 1 ethyl acetate: methanol afforded a viscous oil.

Example 18

2- {3-Chloro-4- [N- [3- (l, 2,3,4-tetrahydro-isoquinolin-2-yl) propyl] -N-methylamino] -2-pyridyl} methylthio-1 H-benzimidazole trihydrochloride

In a manner analogous to that described in Example 2, the title compound was treated with 2- {3-chloro-4- [N- (3-chloropropyl) -N-methylamino] -2-pyridylmethylthio} -1 H-. benzimidazole and 1,2,3,4-tetrahydroisoquinoline. After conversion to the trihydrochloride, a m.p. 239-240 ° C (dec) product is obtained.

Example 19

2- {3-Chloro-4- [N- [3- (N-benzyl-N-methylamino) propyl] -N-methylamino] -2-pyridylmethylthio} -1H-benzimidazole trihydrochloride

The title compound was obtained in a manner analogous to that described in Example 1, using 2- {3-chloro-4- [N- (3-chloropropyl) -N-methylamino] -2-pyridylmethylthio} -1 H-. benzimidazole and N-methyl-N-benzylamine. After chromatography on silica gel and conversion to the trihydrochloride, an amorphous powder melting at 228-230 ° C is obtained.

Example 20

2- {3-Chloro-4- [N- [3- (6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-yl) propyl] -N-methylamino] -2-pyridyl -methylthio} -1H-benzimidazole trihydrochloride In a manner analogous to that described in Example 1, the title compound was 2- {3-chloro-4- [N- (3-chloropropyl) -N-methylamino]. ] -2-pyridylmethylthio} -1H-benzimidazole and 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline. Chromatography on silica gel and elution with petroleum ether / ethyl acetate / methanol (2: 5: 1) afforded a dense yellowish oil.

Example 27

2- {3-Chloro-4- [N- [3- (4-benzyl-piperidino) -propyl] -N-methyl-amino] -2-pyridylmethyl-thio} -1H-benzimidazole trihydrochloride

The title compound was obtained in a manner analogous to that described in Example 1, using 2- {3-chloro-4- [N- (3-chloropropyl) -N-methylamino] -2-pyridylmethylthio} -1H-. benzimidazole and

Prepared by reaction of 4-benzylpiperidine. Chromatography on silica gel, ethyl acetate: 4: 1

Elution with toluene / methanol and conversion to the trihydrochloride afforded a dense, yellowish oil.

Preparation of starting materials

A) 2- {3-Chloro-4- [N- (2-chloroethyl) -N-methylamino] -2-pyridylmethylthio} -1H-benzimidazole dihydrochloride

1. 3-Chloro-4- [N- (2-hydroxyethyl) -N-methylamino] -2-hydroxymethylpyridine

A mixture of 2.5 g of 3,4-dichloro-2- (hydroxymethyl) -pyridine (J. Med. Chem., 1989, 32, 1970) and 30 ml of 2- (methylamino) -ethanol in a steel autoclave. heat at 160 ° C for 1 h. The excess amine was distilled off under high vacuum, and the residue was chromatographed on silica gel eluting with dichloromethane: methanol (95: 5). 2.3 g of a yellowish oil are obtained.

2. 3-Chloro-4- [N- (2-chloroethyl) -N-methylamino] -2-chloromethylpyridine hydrochloride

A solution of 3-chloro-4- [N- (2-hydroxyethyl) -N-methylamino] -2-hydroxymethylpyridine (2.3 g) in dichloromethane (30 ml) at 0 ° C was added thionyl chloride in 20 ml of dichloromethane was added dropwise. The temperature was allowed to rise to 20 ° C (20 minutes) and then held at 40 ° C for 30 minutes. The solvent was removed in vacuo and the residue was chromatographed on silica gel eluting with 7: 3 petroleum ether / ethyl acetate (1 mL / l concentrated aqueous ammonium hydroxide). Yield 2.6 g.

3. 1.8 g of 2-mercapto-1H-benzimidazole and 1.1 g of 3-chloro-4- [N- (2-chloroethyl) -N-methylamino] -2- (chloromethyl) pyridine. A solution of hydrochloric acid in isopropanol (40 ml) was heated to reflux for 1.5 hours. The reaction mixture was concentrated in vacuo to 20 ml and diisopropyl ether (20 ml) was added. After a longer period of time, the crystals which are excellent are filtered off and dried in vacuo. 1.2 g of the title compound are obtained, m.p. 202 DEG C. (dec.).

In a manner analogous to the above procedure, 2- {3-chloro-4- [N- (3-chloropropyl) -N-methylamino] -2-pyridylmethylthio} -1H-benzimidazole dihydrochloride is prepared.

B) 2- {3-Chloro-4- [N- (2-chloroethyl) -N-methylamino] -2-pyridylmethylthio} -1H-imidazo [5,4-b] pyridine

0.96 g of 3-chloro-4- [N- (2-chloroethyl) -N-methylamino] -2-chloromethyl-pyridine hydrochloride and 0.5 g of 2-mercaptol-H-imidazo [5 A mixture of 4-b] pyridine in 25 ml of isopropanol was heated at 90 ° C for 4 hours. The reaction mixture was cooled to 0 ° C. The precipitated crystals are filtered off and washed with a little cold isopropanol. The filter cake was dissolved in water (30 mL), diluted with saturated aqueous sodium bicarbonate (20 mL) and extracted with dichloromethane. The collected extracts were evaporated to dryness in vacuo. The crystalline residue was dried under high vacuum. 0.68 g of the title compound is obtained, m.p. 184-185 ° C.

Industrial applicability

The compounds of the formula I and their salts, because of their excellent activity against Helicobacter bacteria, can be used in human medicine for the treatment of Helicobacter bacteria related diseases.

The compounds of the present invention may be used to treat mammals, particularly humans, suffering from Helicobacter bacterial-related diseases, by administering to the affected individual a therapeutically effective and tolerable amount of one or more compounds of formula I or salts thereof.

The present invention also provides compounds of Formula I and pharmaceutically acceptable salts thereof for use in the treatment of diseases associated with Helicobacter bacteria.

It is a further object of the present invention to provide compounds of formula I and pharmaceutically acceptable salts thereof for the preparation of a medicament for the treatment of diseases associated with Helicobacter bacteria.

The present invention also provides pharmaceutical compositions effective against Helicobacter bacteria comprising one or more compounds of formula I and / or pharmaceutically acceptable salts thereof.

Among the Helicobacter strains against which the compounds of the formula I are effective, mention is made in particular of the Helicobacter pylori strain.

The pharmaceutical compositions of the present invention may be prepared by conventional methods known to those skilled in the art. The pharmaceutical compositions of the present invention comprise the compound of formula I and / or its salt as the active ingredient, alone or, preferably, together with suitable pharmaceutical excipients. The pharmaceutical compositions of the present invention may be in the form of tablets, dragees, capsules, emulsions, suspensions, gels or solutions. The pharmaceutical compositions preferably contain from 0.1 to 95% active ingredient.

The choice of excipients in the pharmaceutical compositions of the present invention is within the skill of the art. In addition to solvents, gelling agents, tabletting excipients and other carriers, the pharmaceutical compositions of the present invention may contain, for example, antioxidants, dispersants, emulsifiers, antifoams, flavor enhancers, preservatives, solubilizers, coloring agents and penetrating agents.

The pharmaceutical compositions of this invention may be administered parenterally (e.g., intravenously) or, preferably, orally.

The active compounds of the formula I are generally used in human medicine at a daily dose of about 0.2 to 50 mg / kg body weight, preferably 1 to 30 mg / kg body weight. The above amount of active ingredient may optionally be administered in several, preferably 2-6, portions to achieve the desired effect.

In this regard, it is noted that the compounds of formula I are effective against Helicobacter bacteria in amounts less than the pharmacologically necessary dose to induce gastric acid secretion.

Biological tests

The activity of compounds of formula I against Helicobacter pylori according to the method of Tomoyuki et al. [Antimicrobial Agents and Chemo7

HU 217 298 Β therapy 490-496. (1991)], Columbia agar (oxoid) up-

using a culture time of 4 days. The MGK (minimum inhibitory concentration) values of the compounds of formula I are shown in Table 1 labeled. Test compounds are characterized by number. is a production example Table 1 test compound MGK value example serial number (G / ml) First <1 Second <1 Third <1 4th <1 5th <1 6th <1 9th <1 10th <1 11th <1 12th <1 13th <1 14th <1 15th <1 16th <1 17th <1 18th <1 19th <1 20th <1 21st <1

PATENT CLAIMS

Claims (10)

PATENT CLAIMS 1. (Substituted amino) alkylaminopyridylmethylthiobenzimidazole and imidazo [5,4b] pyridine derivatives of the formula (I): R ¹ is hydrogen; R ² is hydrogen; R ³ is halogen; R ⁴ is C 1-7 alkyl; A is C 1-7 alkylene; X is = N- or = CH-; R ⁵ is C 1 -C 7 alkyl, C 3 -C 8 cycloalkyl, or Ar (C 1 -C 4 alkyl); and R ⁶ is C 1 -C 7 alkyl, C 3 -C 8 cycloalkyl or Ar (C 1 -C 4 alkyl); where Ar is phenyl, furyl or phenyl substituted by R ⁷ , R ⁸ and R ⁹ ; obsession R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form an unsubstituted or substituted 6-membered heterocycle, namely piperidino, piperazino, Forms a 1,2,3,4-tetrahydroquinolino or 1,2,3,4-tetrahydroisoquinolino group; wherein the substituted piperidino group is one or two identical or different C 1-4 alkyl, C 1 -C 4 alkoxy, phenyl or R ⁷ , R ⁸ and R ⁹ substituted phenyl and / or phenyl (C 1 -C 4 alkyl) substituents; the piperazino is substituted in the 4-position by C1-4 alkyl, (1-4C) alkoxycarbonyl, phenyl, R ^7, R ⁸ and R ⁹ substituted by phenyl, phenyl (Cl-C4) or on the phenyl ring substituted with R ⁷ , R ⁸ and R ⁹ substituted phenyl (C 1 -C 4 alkyl) or benzhydryl; the substituted 1,2,3,4-tetrahydroquinolino group has one or two identical or different C 1-4 alkyl and / or halogen substituents; the substituted 1,2,3,4-tetrahydroisoquinolino group on the benzene ring has one or two hydroxy, C 1 -C 4 alkoxy and / or di (C 1 -C 4 alkyl) amino substituents; R ⁷ is hydrogen, C 1 -C 4 alkyl, C 1-4 alkoxy, halogen or nitro; R ⁸ is hydrogen, C 1 -C 4 alkyl, C 1-4 alkoxy, halogen or nitro; and R ⁹ is hydrogen or trifluoromethyl and salts thereof. Compounds of formula (I) and salts thereof according to claim 1, wherein R ¹ is hydrogen, R ² is hydrogen, R ³ is chlorine, R ⁴ is C 1 -C 4 alkyl, A is ethylene or propylene, and X = CH-. Compounds of formula (I) according to claim 1, and salts thereof, wherein R ¹ is hydrogen; R ² is hydrogen; R ³ is halogen; R ⁴ is C 1 -C 4 alkyl; A is C 2 -C 4 alkylene; and X is = N- or = CH-; R ⁵ is C 1-4 alkyl or Aryl-C4) alkyl; and R ⁶ is Ar (C 1 -C 4) alkyl; Ar is phenyl, furyl or phenyl substituted by R ⁷ , R ⁸ and R ⁹ ; or R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form an unsubstituted or substituted 6-membered heterocycle, namely piperidino, piperazino, 1,2,3,4-tetrahydroquinolin-1-yl or 1,2,3,4-tetrahydroisoquinolin-2-yl; wherein the substituted piperidino is one or two identical or different C 1-4 alkyl, C 1-4 alkoxy, phenyl, R ⁷ , R ⁸ and R ⁹ substituted phenyl and / or phenyl (C 1-4) substituted alkyl); the piperazino is substituted in the 4-position by C1-4 alkyl, (1-4C) alkoxycarbonyl, phenyl, R ^7, R ⁸ and R ⁹ substituted by phenyl, phenyl (Cl-C4) - represents a phenyl (C 1 -C 4 alkyl) or benzhydryl group substituted by R ⁷ , R ⁸ and R ⁹ in the phenyl ring; the substituted 1,2,3,4-tetrahydroquinolino group is one or two, the same or different, HU 217 298 Β C 1 -C 4 alkyl and / or halogen; the substituted 1,2,3,4-tetrahydroisoquinolino group on the benzene ring has one or two hydroxy, C 1 -C 4 alkoxy and / or di (C 1 -C 4 alkyl) amino substituents; R7 is hydrogen, (C1-C4) -alkyl, (C1-C4) -alkoxy, halogen or nitro; R ⁸ is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen or nitro; and R ⁹ is hydrogen or trifluoromethyl. Compounds of formula I according to claim 1, and salts thereof, wherein R ¹ is hydrogen; R ² is hydrogen; R ³ is chlorine; R ⁴ is C 1 -C 4 alkyl; A is ethylene or propylene; and X is = CH-; and R ⁵ is C 1 -C 4 alkyl or benzyl; and R ⁶ is Ar (Cl-C4 alkilj group; Ar is phenyl or furyl; obsession R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form an unsubstituted or substituted 6-membered heterocycle, namely piperidino, piperazino, Forms a 1,2,3,4-tetrahydroisoquinolino group, wherein the substituted piperidino group has a phenyl or benzyl substituent; the substituted piperazino group in the 4-position carries a phenyl, R ⁷ , R ⁸ and R ⁹ substituted phenyl or benzyl substituent; and the substituted 1,2,3,4-tetrahydroisoquinolino group has one or two C 1 -C 4 alkoxy substituents on the benzene ring; and R ⁷ is hydrogen or C 1-4 alkoxy; R ⁸ is hydrogen; and R ⁹ is hydrogen. A process for the preparation of a compound of formula (I) according to claim ¹ , wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , X and A are as defined in claim 1, and salts thereof characterized in that a compound of formula IV, wherein R ¹ , R ² , R ³ , R ⁴ , X and A are as defined above and Z is a suitable leaving group, is reacted with an amine of formula HNR ⁵ R ⁶ wherein R ⁵ and R ⁶ are as defined in claim 1 and optionally converting a compound of formula (I) into a salt and / or liberating a compound of formula (I) in a salt. 6. A pharmaceutical composition comprising one or more compounds of the formula I as claimed in claim 1 and / or a pharmaceutically acceptable salt thereof. Compounds of formula I according to claim 1 and / or pharmaceutically acceptable salts thereof for use against Helicobacter bacteria. Compounds of the formula I according to claim 1 and / or pharmaceutically acceptable salts thereof for use in the treatment and / or prevention of diseases of the stomach and / or intestines. Use of a compound of formula (I) and / or pharmaceutically acceptable salts thereof according to claim 1 for the preparation of a medicament for the treatment of diseases associated with Helicobacter bacteria. Use of a compound of formula (I) according to claim 1 and / or pharmaceutically acceptable salts thereof for the preparation of a medicament for the treatment and / or prevention of diseases of the stomach and / or intestines.